9TYE
Crystal structure of a phosphocoumarin derivative in complex with human carbonic anhydrase II
This is a non-PDB format compatible entry.
Summary for 9TYE
| Entry DOI | 10.2210/pdb9tye/pdb |
| Descriptor | Carbonic anhydrase 2, ZINC ION, 7-methoxy-2-oxidanyl-3,4-dihydro-1,2$l^{5}-benzoxaphosphinine 2-oxide, ... (5 entities in total) |
| Functional Keywords | inhibitor, phosphocoumarin, carbonic anhydrase, complex, lyase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 29658.70 |
| Authors | |
| Primary citation | Nocentini, A.,Giovannuzzi, S.,Alterio, V.,Bonardi, A.,Barons, R.,Zalubovskis, R.,Eldehna, W.M.,Aronne, R.,Esposito, D.,Luchinat, E.,De Simone, G.,Bartolucci, G.,Gratteri, P.,Mori, M.,Supuran, C.T. Discovery of a Mixed and Prodrug-Like Inhibition Mechanism for Phosphocoumarins and Phosphoquinolinones against Human Carbonic Anhydrases. J.Med.Chem., 2026 Cited by PubMed Abstract: Phosphocoumarins and a first-in-class unsubstituted phosphoquinolinone are disclosed as previously unrecognized carbonic anhydrase (CA) inhibitors, displaying multimodal inhibition within a tunable coumarin-like scaffold. Acidic phosphocoumarins display inhibition of physiologically relevant human CAs, particularly tumor-associated isoforms IX and XII (Ks: 0.08-0.28 μM) through a composite, two-step mechanism: the ligand first anchors the zinc-bound water molecule before displacing it to directly coordinate the catalytic zinc ion, without CA-mediated hydrolysis. Conversely, a methyl-ester phosphocoumarin functions as an isoform-selective prodrug, undergoing CA-mediated cyclic phosphoester hydrolysis to selectively generate a potent hCA IX/XII inhibitor (Ks: 54-62 nM), whereas the phosphoquinolinone acts as a direct binder (Ks: 0.18-0.29 μM vs hCA IX/XII). The complementary mechanisms are supported by QM/MM and long-time scale MD simulations, crystallographic studies, P NMR, HRMS, and MS/MS. Selected derivatives exhibit low-micromolar antiproliferative activity and induce apoptosis in cancer cells, fostering phosphorus-heterocycles as a mechanistically rich platform for isoform-selective CA inhibition and targeted drug design. PubMed: 42055938DOI: 10.1021/acs.jmedchem.6c00915 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.65 Å) |
Structure validation
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